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NF-Κb Dysregulation in Microrna-146A–Deficient Mice NF-κB dysregulation in microRNA-146a–deficient mice drives the development of myeloid malignancies Jimmy L. Zhaoa,1, Dinesh S. Raoa,b,1, Mark P. Boldinc, Konstantin D. Taganovd, Ryan M. O’Connella, and David Baltimorea,2 aDivision of Biology, California Institute of Technology, Pasadena, CA 91125; bDepartment of Pathology and Laboratory Medicine, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095; cDepartment of Molecular and Cellular Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010; and dRegulus Therapeutics Inc., San Diego, CA 92121 Contributed by David Baltimore, April 25, 2011 (sent for review February 28, 2011) − − MicroRNA miR-146a has been implicated as a negative feedback tumor phenotype in miR-146a / mice and NF-κB dysregulation regulator of NF-κB activation. Knockout of the miR-146a gene in was uncertain because of the multiple potential targets of miR- C57BL/6 mice leads to histologically and immunophenotypically 146a in different molecular pathways. Here, we focus on char- defined myeloid sarcomas and some lymphomas. The sarcomas acterizing the incidence, cellular lineage, and transplantability of are transplantable to immunologically compromised hosts, show- the tumors, and to understand the molecular basis of oncogenesis. We have found that when they are allowed to age naturally, ing that they are true malignancies. The animals also exhibit −/− chronic myeloproliferation in their bone marrow. Spleen and mar- miR-146a mice on a pure C57BL/6 background develop a fl row cells show increased transcription of NF-κB–regulated genes chronic in ammatory phenotype with progressive myeloprolif- and tumors have higher nuclear p65. Genetic ablation of NF-κB p50 eration involving both the spleen and the bone marrow, which suppresses the myeloproliferation, showing that dysregulation of eventually progresses to splenic myeloid sarcoma and bone NF-κB is responsible for the myeloproliferative disease. marrow failure at about 18 mo of age. Lymphomas of either a B-cell lineage or a mixed T- and B-cell lineage are also observed − − in older miR-146a / mice at a much higher frequency than in inflammation | cancer | myelofibrosis | noncoding RNA wild-type animals. Myeloproliferation in miR-146a–deficient mice are driven primarily by the action of NF-κB because reduction in icroRNAs are a group of ∼19- to 23-nucleotide long non- the NF-κB level by deletion of the NF-κB subunit p50 effectively IMMUNOLOGY Mcoding RNAs that repress target gene expression by a suppresses the pathology. Thus, we have provided genetic evi- combination of mRNA degradation and translation inhibition dence that miR-146a functions as a tumor suppressor in both (1). Recent studies have revealed important physiological roles myeloid and lymphoid cells and that chronic NF-κB activation as of miRNAs in many aspects of mammalian hematopoiesis and a result of miR-146a–deficiency is responsible for driving the immune cell function, and their altered expression has been myeloproliferative disease, which can progress to malignant mye- linked to pathological conditions of the immune system, such as loid sarcoma. hematologic cancers and autoimmunity (2–4). Chronic inflammation contributes to cancer initiation and Results progression. Among a myriad of proposed mechanisms linking miR-146a Knockout Mice Develop Myeloid and Lymphoid Malig- fl κ fi in ammation to cancer, NF- B has been identi ed as a key nancies. The miR-146a–deficient pure C57BL/6 mouse was made fl mediator of in ammation-induced carcinogenesis (5). Moreover, by deleting about 300 base pairs of genomic DNA fragment κ constitutive NF- B activation is frequently detected in many containing the miR-146a precursor (12). The miR-146a–deficient types of lymphoid and myeloid malignancies (6, 7). Hence, un- mice (homozygous knockouts, designated as miR-146a KO) were κ derstanding how NF- B activity is down-regulated has been born at the expected Mendelian frequency and appeared to be a focus of study with important advances in recent years (8). In normal at birth. However, starting at about 5 to 6 mo of age, they κ particular, NF- B regulation by noncoding RNAs has recently developed progressively enlarged spleens. By 18 to 22 mo of age, begun to be characterized. A few years ago, we carried out a 80% of the KO mice were moribund and were culled for analysis. κ microarray screen to identify miRNAs induced by NF- B acti- However, the entire cohort of age-matched littermate C57BL/6 vation and miR-146a was discovered to be one of the miRNAs (WT) control mice, except for one case of thymoma and one case induced by LPS in a human monocytic cell line. The induction of seizure, were still alive and healthy (Fig. S1A). On necropsy, of miR-146a was shown to be NF-κB–dependent, and upon KO mice demonstrated various degrees of splenomegaly, with KO induction, miR-146a functioned to directly down-regulate TNF spleens on average weighing six to seven times more than wild- receptor-associated factor 6 (TRAF6) and IL-1 receptor-associated type spleens (Fig. S1 B and C). By FACS analysis, splenomegaly kinase 1 (IRAK1), two of the signal transducers in the NF-κB was correlated with a massive expansion of the CD11b+ myeloid activation pathway (9). Based on this study and others (10, 11), we population (Fig. S1 D–F). Expanded splenic hematopoiesis was hypothesized that miR-146a, by repressing TRAF6 and IRAK1, also noted based on the increased Ter119+ erythroid precursor may have an effect on NF-κB activation, dampening or termi- population in the spleen. About 40% of the mice demonstrated nating an inflammatory response via a negative-feedback loop. To distinct splenic tumors (Fig. 1 A and B). The majority of these definitively characterize the function of miR-146a in vivo and tumors displayed the histologic appearance of a myeloid sarcoma directly test the hypothesis that miR-146a is a negative regulator of the NF-κB pathway, we generated two independent mouse strains with a targeted germ-line deletion of miR-146a, one on the Author contributions: J.L.Z., D.S.R., and D.B. designed research; J.L.Z. and D.S.R. per- mixed C57BL/6 × 129/sv background and one on the pure C57BL/ formed research; J.L.Z., D.S.R., M.P.B., and K.D.T. contributed new reagents/analytic tools; 6 background. Initial study done primarily with the mixed back- J.L.Z., D.S.R., R.M.O., and D.B. analyzed data; and J.L.Z., D.S.R., and D.B. wrote the paper. −/− −/− ground miR-146a mice showed that miR-146a mice were Conflict of interest statement: D.B. is a member of the board of directors and M.P.B. and −/− hypersensitive to LPS challenge, and aging miR-146a mice K.D.T. are employees of Regulus Therapeutics Inc., a company developing microRNA- developed autoimmune-like disease, myeloid proliferation in based therapeutics. their spleens, and hematopoietic tumors (12). However, the cel- 1J.L.Z. and D.S.R. contributed equally to this work. lular lineage of the tumors and the mechanistic basis of miR- 2To whom correspondence should be addressed. E-mail: [email protected]. – fi 146a de ciency mediated myeloproliferation remained impor- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. tant unanswered questions. In addition, the relationship of the 1073/pnas.1105398108/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1105398108 PNAS Early Edition | 1of6 Downloaded by guest on September 23, 2021 p<0.01 A 60 Myeloid Tumor Lymphoma WT (n=39) 40 KO (n=43) 20 Tumor Incidence (%) Tumor Incidence 0 T W KO B Fig. 1. miR-146a–deficient mice develop myeloid and lymphoid malignancies. Mice were 18- to 22-mo-old miR-146a−/− mice (KO) and sex- and age-matched C57BL/6 control mice (WT). (A) Incidences of mye- CD19 loid and lymphoid malignancies observed CD11b in wild-type (n = 39) and KO (n = 43) mice. (B) Photograph, FACS plot, and histologi- C cal analysis of a representative myeloid tumor from a KO spleen. Panels 3 and 4 show an H&E-stained spleen section. [Scale bars, (Left) 100 μm; (Right)40μm.] Arrows, mitotic figures. (C) Photograph, FACS plot, and histological analysis of a representative B-cell lymphoma from a KO gastrointestinal CD3ε B220 tract. Panels 3 and 5 show an H&E-stained CD19 tumor section; panel 4 shows positive im- munohistochemical staining for B220 [Scale D bars, (Left to Right)100μm in panels 3 and 4 and 40 μm in panel 5.] (D) Photograph, Liv FACS plot, and histological analysis of a representative mixed T- and B-cell lym- phoma from a KO liver. Panels 3–5 show H&E-stained liver sections. Lym, Lymphoma; Lym Liv, relatively uninvolved liver. [Scale bars CD3ε (Left to Right)are400μm, 100 μm, and CD19 40 μm.] (Fig. 1B) (13). FACS analysis of carefully dissected tumors the course of 8 wk, mice receiving KO splenocytes showed a showed that the cells derived from these tumors expressed the progressive increase in signal, culminating in an ∼10- to 20-fold pan-myeloid antigen, CD11b (Fig. 1B). Occasionally, liver and higher signal, indicating a proliferation of the transplanted cells, kidney were also heavily infiltrated by myeloid sarcoma (Fig. S2 but wild-type cells did not (Fig. 2B). Interestingly, recipient A and B). A general role of miR-146a as a tumor-suppressor spleens, kidneys, and livers showed the strongest biolumniscence miRNA in the hematolymphoid system was demonstrated by the signal, indicating the proclivity of transplanted splenic tumor development of lymphomas of a B-cell or a mixed T- and B-cell cells to localize to the same organs where the most significant lineage in the cervical lymph node, gastrointestinal tract, liver, and myeloid tumor pathology was observed in the original KO mice.
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